NF‐κB inducing kinase is a key regulator of inflammation‐induced and tumor‐associated angiogenesis

Abstract Angiogenesis is essential during development and in pathological conditions such as chronic inflammation and cancer progression. Inhibition of angiogenesis by targeting vascular endothelial growth factor (VEGF) blocks disease progression, but most patients eventually develop resistance which may result from compensatory signaling pathways. In endothelial cells (EC) expression of the pro‐angiogenic chemokine CXCL12 is regulated by non‐canonical nuclear factor (NF)‐κB signaling. Here, we report that NF‐κB‐inducing kinase (NIK) and subsequent non‐canonical NF‐κB signaling regulates both inflammation‐induced and tumor‐associated angiogenesis. NIK is highly expressed in endothelial cells (EC) in tumor tissues and inflamed rheumatoid arthritis synovial tissue. Furthermore, non‐canonical NF‐κB signaling in human microvascular EC significantly enhanced vascular tube formation, which was completely blocked by siRNA targeting NIK. Interestingly, Nik‐/‐ mice exhibited normal angiogenesis during development and unaltererd TNFα‐ or VEGF‐induced angiogenic responses, whereas angiogenesis induced by non‐canonical NF‐κB stimuli was significantly reduced. In addition, angiogenesis in experimental arthritis and a murine tumor model was severely impaired in these mice. These studies provide evidence for a role of non‐canonical NF‐κB signaling in pathological angiogenesis, and identify NIK as a potential therapeutic target in chronic inflamma...
Source: The Journal of Pathology - Category: Pathology Authors: Tags: Original Article Source Type: research